Nonobstructive ileus, signifying the impairment of coordinated propulsive intestinal motility, remains a frequently documented and almost inevitable consequence of open abdominal surgery and sepsis. Despite the frequency and major impact of ileus on morbidity and mortality, the exact underlying molecular and cellular mechanisms of this important clinical conundrum are still ill defined. Animal models suggest that both neuronal and local inflammatory responses within the intestinal muscularis mechanistically contribute to intestinal ileus. The neuronal mechanism appears to involve the enhanced release of nitric oxide from inhibitory motor neurons. Likewise, nitric oxide and prostaglandins are released from inflammatory cells (macrophages and monocytes) via the induction of nitric oxide synthase (iNOS) and cyclooxygenase-2. Recently, preliminary data have confirmed the existence of an intraoperative local muscularis inflammatory response during surgery in human patients.